As a method for producing (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole having an antiulcer activity [hereinafter sometimes to be referred to as an (R)-form] or (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole having an antiulcer activity [hereinafter sometimes to be referred to as an (S)-form], for example, Japanese Patent Application under PCT laid-open under kohyo No. Hei 11-508590 (WO 97/02261) describes a method for optically purifying a product prepared to be enriched in one enantiomer, which comprises adding a product prepared to contain either (+)-enantiomer or (−)-enantiomer in a greater amount than the other, namely, product prepared to be enriched in one enantiomer, to a solvent, selectively precipitating a racemic compound from the solvent utilizing the crystallinity of racemates, filtering and removing the precipitated racemic compound and removing the solvent to give a single enantiomer having an increased optical purity.
When an (R)-form or (S)-form is to be produced by asymmetric synthesis, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (hereinafter sometimes to be referred to as a sulfide form) is subjected to asymmetric oxidization to give the objective (R)- or (S)-form. In this case, an excess reaction product, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]benzimidazole (hereinafter sometimes to be referred to as a sulfone form), is produced. Accordingly, the (R)-form or (S)-form obtained by asymmetric synthesis generally includes an unreacted sulfide form as an analogous substance and a sulfone form as an excess. reaction product.
Generally, a sulfone form present in sulfoxide having an antiulcer activity is difficult to remove. For example, JP-A-2000-16992 discloses that, once sulfone is produced, the yield of the objective sulfoxide decreases, and separation and purification is problematically difficult because the physico-chemical properties of the both are extremely similar to each other. Similarly in the case of an (R)-form or (S)-form, a column chromatography treatment and the like are essential for removing a sulfone form present as an analogous substance.
For example, in Example 21 of Japanese Patent Application under PCT laid-open under kohyo No. Hei 10-504290 (WO 96/02535), flush chromatography was applied to obtain the object substance from a solution containing a large amount of (−)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole (11% of sulfide form and 7% of sulfone form present as analogous substances), after which various steps are applied to obtain the 99.5% ee objective substance in a yield of 29%. In Example 22 of this publication, flush chromatography was applied to obtain the objective substance from a solution containing a large amount of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]sulfinyl]benzimidazole (13% of sulfide form and 8% of sulfone form present as analogous substances), after which various steps are applied to obtain the 99.6% ee objective substance in a yield of 14%.
As evidenced, conventional methods require industrially disadvantageous operations such as chromatography and the like are necessary for removing a sulfone form and the like, and the yield of the objective substance remains at a low level.
The conventional production methods are associated with problems that they indispensably require purification by column chromatography and the like to remove a sulfone form that resists separation and purification, and the objective optically active sulfoxide form shows a low enantiomer excess (optical purity) and low yield. Therefore, a production method of an (R)-form or (S)-form having an antiulcer activity, has been demanded which is industrially advantageous from the aspects of the amount of analogous substance present therein, enantiomer excess, yield, productivity, economic efficiency and the like.